1. Field of the Invention
The present invention relates to a metallo-β-lactamase inhibitor comprising a maleic acid compound as an effective ingredient, and more particularly, it relates to a pharmaceutical composition to improve the effectiveness against metallo-β-lactamase producing resistant bacteria in combination with β-lactam antibiotics for the therapy of bacterial infection in animal or human being and a method for treating the bacterial infections.
2. Background Art
β-lactamase plays an important role in the acquisition of resistance against β-lactam antibiotics in bacteria. Particularly, metallo-β-lactamases which contains zinc at their active center and exhibits wide ranges of substrate specificities are at issue due to the fact that the metallo-β-lactamases also hydrolyze carbapenem antibiotics which are relatively stable to serine-β-lactamase. In fact, metallo-β-lactamase producing bacteria are a menace to clinically important β-lactam pharmaceuticals due to the acquisition of resistance to such pharmaceuticals. Metallo-β-lactamases have been confirmed in a variety of bacterial strains such as Bacillus cereus, Bacteriocides fragilis, Escherichia coli, Aeromonas hydrophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Serratia marcescens, Stenotrophomonas maltophilia, Shigella flexneri, Alcaligenes xylosoxidans, Legionella gormanii, Chryseobacterium meningosepticum, Chryseobacterium indologenes, Acinetobacter baumannii, Citrobacter freundii, and Enterobacter cloacae. Particularly, Pseudomonas aeruginosa causes serious problem because of its conspicuous multidrug resistance. Clavulanic acid, sulbactam, and tazobactam which are now used as β-lactamase inhibitors are effective against serine-β-lactamase having serine as an active center, but these drugs exhibit not inhibiting effect on metallo-β-lactamases.
Therefore, metallo-β-lactamase inhibitors have been increasingly necessitated in order to recover the effectiveness of β-lactam antibiotics such as imipenem against metallo-β-lactamase producing resistant bacteria.
Since a metallo-β-lactamase coded on a transferable plasmid has first been reported in Pseudomonas aeruginosa, many compounds have been reported as those having metallo-β-lactamase inhibiting activities. In WO98/17639, WO97/30027, WO98/40056, WO98/39311, and WO97/10225, certain β-thiopropionyl-amino acid derivatives have been described together with their uses as the inhibitor against the metallo-β-lactamases. Also, several literatures disclose thiols and thioesters as metallo-β-lactamase inhibitors (Biol. Pharm. Bull. 1997, 20, 1136; FEMS Microbiology Letters 1997, 157, 171; Antimicrob. Agents Chemother. 1997, 41, 135; Chem. Commun. 1998, 1609; Biochem. J. 1998, 331, 703; WO00/076962). Furthermore, there are disclosed succinic acid compounds as the metallo-β-lactamase inhibitors in WO01/030148 and WO01/030149. In addition, there is a literature in which general situations on various metallo-β-lactamase inhibitive compounds and metallo-β-lactamase producing bacteria are described (Clin. Microbiol. Rev. 2005, 18, 306). However, none of the literatures described above disclose or suggest the maleic acid derivatives as the compounds of the present invention.
In order to exert the effect of the metallo-β-lactamase inhibitor against the metallo-β-lactamase producing resistant bacteria actually in clinical practice, it is essential to recover the effectiveness in combination with β-lactam antibiotics. However, there has hitherto been described scarcely such combination effect against bacterial species including Pseudomonas aeruginosa which is at issue in the medical field. There is at present no metallo-β-lactamase inhibitor which is effective on infections in human beings and animals.
With respect to the maleic acid derivatives, dimethyl maleate has been disclosed in Japanese Patent Laid-Open Publication No. 57-207245, dimethyl maleate and diethyl maleate, i.e. the compounds having the general formula (I) wherein M1 represents a hydrogen atom, and the like have been disclosed in Acta Chem. Scand. 1964, 18, 1276, and 3-methyl-2-tetradecanyl maleate has been disclosed in Japanese Patent Publication No. 7-91213. However, the salts or esters having a group which can be hydrolyzed in vivo of these derivatives have not been described in them.
Also, there is disclosed in Bioorg. Med. Chem., 2000, 8, 571 2-hydroxymethyl-3-tetradecanyl maleate but not the other 2-hydroxymethyl-3-lower alkyl maleate. Furthermore, there is disclosed in J. Am. Chem. Soc. 1955, 77, 6702 dicarboxylic acids having a cyclic alkyl group in the side chain, which are mono-substituted fumarate derivatives but not maleate derivatives. There is disclosed in J. Org. Chem. 1984, 49, 1985 maleic acid derivatives, one of which has an alkylthio substituent, but the other has an alkenyl group. There are disclosed in WO 91/08775 and Tetrahedron Lett. 1988, 29, 3869 maleic acid ester compounds mono-substituted with an alkoxy group, but a carboxylic acid thereof, i.e. the compound having the general formula (I) wherein M1 represents a hydrogen atom, or a salt thereof have not been disclosed in these literatures. In addition, a compound having a dihydrofuranyl group has been described in Nord. Pulp Pap. Res. J. 1994, 9, 84, and a compound having a pyridinium group has been described in Angew. Chem., 1990, 102, 1164, but no metallo-β-lactamase inhibiting activity has been indicated in therein.